Surfactant replacement therapy in neonates is currently achieved through endotracheal intubation and liquid bolus instillation. High efficiency delivery of aerosolized surfactant is proposed as a technique to improve airway distribution of the surfactant and prevent endotracheal intubation in cases where noninvasive ventilation (NIV) is the preferred respiratory support strategy. Primary limitations of aerosolized surfactants are currently very low lung delivery efficiencies (typically ~1%), long delivery times (~3 hours for mesh nebulizers), and poor distribution of the surfactant to the alveolar region. The goal of this study is to develop formulations and devices for the effective delivery of aerosolized surfactants to the lungs of infants using the nose-to-lung (N2L) route thereby avoiding intubation. To achieve high efficiency lung delivery, the excipient enhanced growth (EEG) approach will be used in which submicrometer particles are formed through spray drying and contain the surfactant and a hygroscopic excipient. The initial small size of the aerosolized particles allows for effective penetration through the new delivery device and infant upper airways. Inclusion of the hygroscopic excipient in the primary particles fosters aerosol size increase inside the airways and effective deposition in the alveolar region. This approach was successfully employed by our group to improve N2L aerosol delivery in adults. The aerosol will be generated using new EEG surfactant powder formulations together with new low-flow and low-volume dry powder inhalers, which are developed and optimized using a combination of computational fluid dynamics (CFD), rapid prototyping, and in vitro experiments. Functionality of the new surfactant aerosol will be assessed in surfactant depletion animal models and compared with liquid instillation. The following aims are proposed to develop this new therapeutic approach: Specific Aim 1. Develop an excipient enhanced growth (EEG) formulation of a lung surfactant that can be efficiently aerosolized, increase in aerodynamic size within the airways, and maintain surfactant function. Specific Aim 2. Develop and optimize a device for generating and administering surfactant aerosols to infants using the noninvasive nose-to-lung (N2L) route and achieving high efficiency lung delivery. Specific Aim 3. Adapt the N2L aerosol delivery device and test EEG surfactant aerosol efficacy in an infant- size ferret model compared with surfactant instillation in terms of oxygenation, lung distribution and histology. Outcomes and Impact. Successful delivery of aerosolized surfactant will avoid the side effects associated with instillation in already compromised infant airways. Efficient N2L delivery will allow for expanded use of NIV respiratory support techniques, thereby avoiding the greater risks associated with intubation and liquid bolus instillation. In addition to respiratory distress syndrome in infants, improved surfactant delivery to the alveolar region may also aid the treatment of other lung conditions such as pneumonia and viral bronchiolitis.